Transcriptomic Changes Induced by Mycophenolic Acid in Gastric Cancer Cells

Overview

Journal Am J Transl Res

Specialty General Medicine

Date 2013 Dec 19

PMID 24349619

Citations 15

Authors

Boying Dun

Ashok Sharma

Heng Xu

Haitao Liu

Shan Bai

Lingwen Zeng

Jin-Xiong She

Affiliations

Soon will be listed here.

Abstract

Background: Inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA) can inhibit proliferation and induce apoptosis in cancer cells. This study investigated the underlying molecular mechanisms of MPA's anticancer activity.

Methods: A gastric cancer cell line (AGS) was treated with MPA and gene expression at different time points was analyzed using Illumina whole genome microarrays and selected genes were confirmed by real-time RT-PCR.

Results: Transcriptomic profiling identified 1070 genes with ≥2 fold changes and 85 genes with >4 fold alterations. The most significantly altered biological processes by MPA treatment include cell cycle, apoptosis, cell proliferation and migration. MPA treatment altered at least ten KEGG pathways, of which eight (p53 signaling, cell cycle, pathways in cancer, PPAR signaling, bladder cancer, protein processing in ER, small cell lung cancer and MAPK signaling) are cancer-related. Among the earliest cellular events induced by MPA is cell cycle arrest which may be caused by six molecular pathways: 1) up-regulation of cyclins (CCND1 and CCNE2) and down-regulation of CCNA2 and CCNB1, 2) down-regulation of cyclin-dependent kinases (CDK4 and CDK5); 3) inhibition of cell division related genes (CDC20, CDC25B and CDC25C) and other cell cycle related genes (MCM2, CENPE and PSRC1), 4) activation of p53, which activates the cyclin-dependent kinase inhibitors (CDKN1A), 5) impaired spindle checkpoint function and chromosome segregation (BUB1, BUB1B, BOP1, AURKA, AURKB, and FOXM1); and 6) reduction of availability of deoxyribonucleotides and therefore DNA synthesis through down-regulation of the RRM1 enzyme. Cell cycle arrest is followed by inhibition of cell proliferation, which is mainly attributable to the inhibition of the PI3K/AKT/mTOR pathway, and caspase-dependent apoptosis due to up-regulation of the p53 and FAS pathways.

Conclusions: These results suggest that MPA has beneficial anticancer activity through diverse molecular pathways and biological processes.

Citing Articles

Prenatal p25-activated Cdk5 induces pituitary tumorigenesis through MCM2 phosphorylation-mediated cell proliferation.

Huang Y, Wang Q, Zhou W, Jiang Y, He K, Huang W Neoplasia. 2024; 57:101054.

PMID: 39366214 PMC: 11489071. DOI: 10.1016/j.neo.2024.101054.

Physicochemical Characterization and In Vitro Activity of Poly(ε-Caprolactone)/Mycophenolic Acid Amorphous Solid Dispersions.

Sanchez-Aguinagalde O, Sanchez-Rexach E, Polo Y, Larranaga A, Lejardi A, Meaurio E Polymers (Basel). 2024; 16(8).

PMID: 38675007 PMC: 11054924. DOI: 10.3390/polym16081088.

Repurposed Drugs in Gastric Cancer.

Araujo D, Ribeiro E, Amorim I, Vale N Molecules. 2023; 28(1).

PMID: 36615513 PMC: 9822219. DOI: 10.3390/molecules28010319.

Microglia-Dependent and Independent Brain Cytoprotective Effects of Mycophenolate Mofetil During Neuronal Damage.

Kleine J, Hohmann U, Hohmann T, Ghadban C, Schmidt M, Laabs S Front Aging Neurosci. 2022; 14:863598.

PMID: 35572146 PMC: 9100558. DOI: 10.3389/fnagi.2022.863598.

CENPE promotes glioblastomas proliferation by directly binding to WEE1.

Ma C, Wang J, Zhou J, Liao K, Yang M, Li F Transl Cancer Res. 2022; 9(2):717-725.

PMID: 35117417 PMC: 8799097. DOI: 10.21037/tcr.2019.11.40.

References

Seillier M, Peuget S, Gayet O, Gauthier C, NGuessan P, Monte M . TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death. Cell Death Differ. 2012; 19(9):1525-35. PMC: 3422476. DOI: 10.1038/cdd.2012.30. View

Dun B, Xu H, Sharma A, Liu H, Yu H, Yi B . Delineation of biological and molecular mechanisms underlying the diverse anticancer activities of mycophenolic acid. Int J Clin Exp Pathol. 2013; 6(12):2880-6. PMC: 3843268. View

Lerner A, Upton J, Praveen P, Ghosh R, Nakagawa Y, Igbaria A . IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab. 2012; 16(2):250-64. PMC: 4014071. DOI: 10.1016/j.cmet.2012.07.007. View

Jackson R, Weber G, MORRIS H . IMP dehydrogenase, an enzyme linked with proliferation and malignancy. Nature. 1975; 256(5515):331-3. DOI: 10.1038/256331a0. View

Falcon S, Gentleman R . Using GOstats to test gene lists for GO term association. Bioinformatics. 2006; 23(2):257-8. DOI: 10.1093/bioinformatics/btl567. View

Morgensztern D, McLeod H . PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs. 2005; 16(8):797-803. DOI: 10.1097/01.cad.0000173476.67239.3b. View

Domhan S, Muschal S, Schwager C, Morath C, Wirkner U, Ansorge W . Molecular mechanisms of the antiangiogenic and antitumor effects of mycophenolic acid. Mol Cancer Ther. 2008; 7(6):1656-68. DOI: 10.1158/1535-7163.MCT-08-0193. View

Takebe N, Cheng X, Fandy T, Srivastava R, Wu S, Shankar S . IMP dehydrogenase inhibitor mycophenolate mofetil induces caspase-dependent apoptosis and cell cycle inhibition in multiple myeloma cells. Mol Cancer Ther. 2006; 5(2):457-66. DOI: 10.1158/1535-7163.MCT-05-0340. View

Sharma A, Podolsky R, Zhao J, McIndoe R . A modified hyperplane clustering algorithm allows for efficient and accurate clustering of extremely large datasets. Bioinformatics. 2009; 25(9):1152-7. PMC: 2672630. DOI: 10.1093/bioinformatics/btp123. View

10.

Smyth G . Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2006; 3:Article3. DOI: 10.2202/1544-6115.1027. View

11.

Nigg E . Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle. Bioessays. 1995; 17(6):471-80. DOI: 10.1002/bies.950170603. View

12.

Gonzalez R, Ferrin G, Aguilar-Melero P, Ranchal I, Linares C, Bello R . Targeting hepatoma using nitric oxide donor strategies. Antioxid Redox Signal. 2012; 18(5):491-506. DOI: 10.1089/ars.2011.4476. View

13.

Morath C, Schwenger V, Beimler J, Mehrabi A, Schmidt J, Zeier M . Antifibrotic actions of mycophenolic acid. Clin Transplant. 2006; 20 Suppl 17:25-9. DOI: 10.1111/j.1399-0012.2006.00597.x. View

14.

Huang B, Eberstadt M, Olejniczak E, Meadows R, Fesik S . NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain. Nature. 1996; 384(6610):638-41. DOI: 10.1038/384638a0. View

15.

Millan O, Oppenheimer F, Brunet M, Vilardell J, Rojo I, Vives J . Assessment of mycophenolic acid-induced immunosuppression: a new approach. Clin Chem. 2000; 46(9):1376-83. View

16.

Tarca A, Draghici S, Khatri P, Hassan S, Mittal P, Kim J . A novel signaling pathway impact analysis. Bioinformatics. 2008; 25(1):75-82. PMC: 2732297. DOI: 10.1093/bioinformatics/btn577. View

17.

Laoukili J, Kooistra M, Bras A, Kauw J, Kerkhoven R, Morrison A . FoxM1 is required for execution of the mitotic programme and chromosome stability. Nat Cell Biol. 2005; 7(2):126-36. DOI: 10.1038/ncb1217. View

18.

Kim J, Goo S, Chung H, Yang H, Yong T, Lee K . Interaction of beta-giardin with the Bop1 protein in Giardia lamblia. Parasitol Res. 2005; 98(2):138-44. DOI: 10.1007/s00436-005-0040-8. View

19.

Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A . STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2012; 41(Database issue):D808-15. PMC: 3531103. DOI: 10.1093/nar/gks1094. View

20.

Allison A, Eugui E . Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation. 2005; 80(2 Suppl):S181-90. DOI: 10.1097/01.tp.0000186390.10150.66. View